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Influence of Indomethacin on Steroid Metabolism

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Influence of Indomethacin on Steroid Metabolism H OH metabolites OH Article Influence of Indomethacin on Steroid Metabolism: Endocrine Disruption and Confounding Effects in Urinary Steroid Profiling of Anti-Doping Analyses Anna Stoll 1 , Michele Iannone 2 , Giuseppina De Gregorio 2, Francesco Molaioni 2, Xavier de la Torre 2 , Francesco Botrè 2,3 and Maria Kristina Parr 1,* 1 Institute of Pharmacy (Pharmaceutical and Medical Chemistry), Freie Universität Berlin, 14195 Berlin, Germany; [email protected] 2 Laboratorio Antidoping Federazione Medico Sportiva Italiana, 00197 Rome, Italy; [email protected] (M.I.); [email protected] (G.D.G.); [email protected] (F.M.); [email protected] (X.d.l.T.); [email protected] (F.B.) 3 Synathlon—Quartier Centre, ISSUL—Institut des Sciences du Sport, Université de Lausanne, 1015 Lausanne, Switzerland * Correspondence: [email protected]; Tel.: +49-30-838-51471 Received: 13 September 2020; Accepted: 9 November 2020; Published: 14 November 2020 Abstract: Anabolic androgenic steroids (AAS) are prohibited as doping substances in sports by the World Anti-Doping Agency. Concentrations and concentration ratios of endogenous AAS (steroid profile markers) in urine samples collected from athletes are used to detect their administration. Certain (non-prohibited) drugs have been shown to influence the steroid profile and thereby sophisticate anti-doping analysis. It was shown in vitro that the non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits selected steroid-biotransformations catalyzed by the aldo-keto reductase (AKR) 1C3, which plays a key role in the endogenous steroid metabolism. Kinetic parameters for the indomethacin-mediated inhibition of the AKR1C3 catalyzed reduction in etiocholanolone were determined in vitro using two comparing methods. As NSAIDs are very frequently used (not only) by athletes, the inhibitory impact of indomethacin intake on the steroid metabolism was evaluated, and steroid profile alterations were detected in vivo (one male and one female volunteer). Significant differences between samples collected before, during or after the intake of indomethacin for selected steroid profile markers were observed. The presented results are of relevance for the interpretation of results from doping control analysis. Additionally, the administration of NSAIDs should be carefully reconsidered due to their potential as endocrine disruptors. Keywords: NSAID; inhibition; doping; aldo-keto reductases; endocrine disruption 1. Introduction Anabolic androgenic steroids (AAS) are very frequently used drugs in sports [1]. Their use as doping agents is prohibited in and out of competition by the World Anti-Doping Agency (WADA; class S1 in the WADA prohibited list) [2]. The analytical detection is challenging, especially if so-called pseudo endogenous AAS (e.g., exogenous testosterone) are used as performance enhancing substances, due to their high similarity to the naturally occurring endogenous AAS (EAAS). To detect the misuse of those pseudo endogenous and some synthetic AAS, anti-doping laboratories monitor in a first step, concentrations and concentration ratios of selected EAAS according to the WADA technical document TD2018EAAS in urine samples collected from the athletes [3]. In case of misuse of pseudo endogenous AAS or some synthetic AAS, those steroid profile markers are altered and a confirmative method using gas chromatography combustion isotope-ratio mass-spectrometry (GC-c-IRMS) is Metabolites 2020, 10, 463; doi:10.3390/metabo10110463 www.mdpi.com/journal/metabolites Metabolites 2020, 10, 463 2 of 19 applied. Since it has been shown that ratios of urinary steroids are stable over months and even years in adult humans [4–6] but show interindividual variations, the steroidal module of the Athlete Biological Passport (ABP) was introduced by WADA in 2014 [7]. With this longitudinal monitoring model, it is possible to better detect intraindividual changes, and hence the potential misuse of AAS. However, it was shown that besides various endogenous and exogenous parameters, the intake of selected (non-prohibited) drugs can influence the individual steroid profile and lead to suspicious testing results [8–10]. To better understand how changes in the steroid profile can occur after the intake of specific drugs, it is helpful to understand and further investigate the steroid metabolism and potential points of interference. One enzyme-family which plays a key role in the metabolism of EAAS are aldo-keto-reductases (AKR; Figure1). In this study we focused on the AKR1C3, which is known to oxidize 17-hydroxy steroids to their corresponding 17-oxo metabolites and vice versa. It was reported that the reduction route is favored in vivo [11]. Furthermore, it was reported by Byrns et al. that the non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits the AKR1C3 catalyzed reduction in androst-4-ene-3,17-dione in vitro selectively over the closely related AKR1C2 and AKR1C1 [12,13]. No further investigations have been made on the inhibitory effect of indomethacin on 5β-androstanes metabolized by AKR1C3. As NSAIDs are very frequently used drugs (not only) among athletes [14,15], this work aims to further investigate the influence of indomethacin on the steroid metabolism in vitro and wants to show the relevance of indomethacin on the urinary steroid profile in vivo. Hence, the work consists of an in vitro part and an in vivo application trial. The in vitro experiments were analyzed spectro-fluorometrically in real time and by gas chromatography coupled to a quadrupole-time-of-flight mass spectrometer (GC-QToF) as confirmative tests. For the in vivo part, indomethacin was administered to one male and one female volunteer in therapeutic doses over 14 days. Urine samples before, during and after the administration were collected and analyzed. The results first give ideas on the impact of indomethacin intake on steroid profiles in doping control analysis and its potential mechanism of endocrine disruption. Figure 1. Metabolism of endogenous anabolic androgenic steroids (EAAS); blue and bold: substrates and enzymes used in this publication. 2. Results 2.1. Qualitative Incubation In Vitro With the applied GC-MS (gas chromatography-mass spectrometry) method, all EAAS of interest were sufficiently separated (no interference between steroids was expected to occur simultaneously during the different incubations). All analyzed EAAS standards are depicted in the upper chromatogram Metabolites 2020, 10, 463 3 of 19 in Figure2. For all background incubations (absence of enzyme) no other steroids besides the substrate were detectable. The internal standard (17α-methyltestosterone; substance K in Figure2) was detected in all samples. Figure2 shows chromatograms of samples after enzymatic incubations in solid lines. As no substrate was detected after the incubation of Etio (etiocholanolone, substance D in Figure2) the sample chromatogram (solid line) was superimposed by the chromatogram of the background-incubation (dotted line). A detailed display of chromatograms of all performed incubations and background samples is available as supplementary data (Supplement S1). Chromatograms are displayed as total ion current chromatograms. Hence, peaks originating from the incubation media are also present. This is assumed to be the case for the two big peaks at 8.79 min and at 9.47 min, as both are also present in background-samples (without enzyme). They are hence neglected in the results presentation and discussion. In the following paragraph, detailed outcomes of individual steroid incubations with AKR1C3 (aldo-keto reductase 1C3) will be described. After incubation of 5αAD (5α-androstanedione, substance G in Figure2), small amounts of substrate were detected. In addition, minor amounts of 5 αDHT (5α-dihydrotestosterone, substance H in Figure2) and larger amounts of And (androsterone, substance C in Figure2) and 5 αAdiol (5α-androstane-3α,17β-diol, substance E in Figure2) were detected. All of these compounds have a 5α-androstane structure in common and are highlighted in orange in Figure2. After incubation of 5βAD (5β-androstanedione, substance A in Figure2) no or small amounts of substrate, but peaks corresponding to 5βAdiol (5β-androstane-3α,17β-diol, substance F in Figure2) and Etio (substance D in Figure2), were detected. Furthermore, very minor amounts of 5 βDHT (5β-dihydrotestosterone, substance B in Figure2) were detectable in one of two replicates (not visible in Figure2). All of these compounds have a 5 β-androstane structure in common and are highlighted in green in Figure2. After incubation of AED (androst-4-ene-3,17-dione, substance I in Figure2) with AKR1C3, AED itself and its metabolite T (testosterone, substance J in Figure2) were detected. Both compounds are highlighted in violet in Figure2. After incubation of And (substance C in Figure2) with AKR1C3, peaks corresponding to And and 5αAdiol (substance E in Figure2) were detected. Only minor amounts of the substrate were detected (small peak at 8.36 min with framed retention time (RT) in androsterone chromatogram in Figure2). And and 5αAdiol share a 5α-androstane structure and are hence highlighted in orange in Figure2. After incubation of Etio (substance D in Figure2) the substrate itself was detected in only one of the two replicates (indicated as dotted peak at 8.41 min corresponding to Etio detected in the background sample). The metabolite 5βAdiol (substance F in Figure2) was present in both replicates. As Etio and 5βAdiol share a 5β-androstane structure
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